Compliant tissue sealants

ABSTRACT

An improved barrier or drug delivery system which is highly adherent to the surface to which it is applied is disclosed, along with methods for making the barrier. In the preferred embodiment, the system is compliant, in that it is capable of conforming to the three dimensional structure of a tissue surface as the tissue bends and deforms during healing processes. The barrier or drug delivery systems is formed as a polymeric coating on tissue surfaces by applied a polymerizable monomer to the surface, and then polymerizing the monomer. The polymerized compliant coating preferably is biodegradable and biocompatible, and can be designed with selected properties of compliancy and elasticity for different surgical and therapeutic applications.

This application is a continuation of Ser. No. 09/732,419 filed Dec. 7,2000 now U.S. Pat. No. 6,352,738, which is a continuation of Ser. No.09/477,162 filed Jan. 4, 2000, now U.S. Pat. No. 6,217,894, which is acontinuation of Ser. No. 09/288,207 filed Apr. 8, 1999, now U.S. Pat.No. 6,051,248, which is a continuation of U.S. Ser. No. 08/710,689 filedSep. 23, 1996, now U.S. Pat. No. 5,900,245, which is acontinuation-in-part of International Application No. PCT/US96/03834filed Mar. 22, 1996.

BACKGROUND OF THE INVENTION

The present invention relates to methods and compositions for improvingthe adherence of polymer gels to surfaces, particularly tissue surfaces,and for improving the compliance of the materials.

Locally polymerized gels have been used as barriers and drug deliverydevices for several medical conditions. Adherence of the formed gel tothe tissue can be a problem, especially under surgical conditions, wherethe tissue surface to be treated is typically wet, and may further becovered with blood, mucus or other secretions. Hubbell and co-workershave described two methods for photopolymerizing gels in contact withtissue surfaces. In U.S. Pat. No. 5,410,016, hereby incorporated byreference, application of biodegradable macromers to tissue, followed byphotopolymerization to form a gel, is described. Two methods forphotopolymerizing gels are described. In “bulk” polymerization, asuitable photoinitiator and accessory reagents are solubilized ordispersed in a solution of gelling macromers. On application of light,the entire solution volume crosslinks to form a gel which acts as alocal barrier or drug depot. These gels have substantial adherence tomost surfaces, including tissue surfaces which are merely moist.However, if a confounding layer of fluid is present on the surface whenthe macromer/initiator solution is applied, then the gel may delaminatefrom the surface after its formation.

An alternative way of forming a gel layer on a surface, as described inU.S. Ser. No. 08/024,657, which is hereby incorporated herein byreference, is called the “interfacial” method. In this method, thesurface to be coated is treated with a photoinitiator which adsorbs orabsorbs to the surface. After washing away excess, unabsorbedphotoinitiator, a polymerizable macromer solution is applied to thesurface on exposure to light, polymerization is initiated at thesurface, and progresses outward into the solution to the limit ofdiffusion of the photoinitiator-generated radicals during theirlifespan. Coating thicknesses of up to about 500 micrometers (microns)are routinely obtained. Since they are in effect “grown” from the tissuesurface, such gel layers have excellent adhesion to the tissue surfaceunder difficult conditions, including the presence of thin layers offluid adherent to the surface. The limited thickness of such interfacialgels is desirable in some circumstances, but represents a majorlimitation where gels of substantially greater thickness than 500microns are required, for example, for use in drug delivery, or informing a thick physical barrier between the tissue surface and itssurroundings. In addition to the photopolymerizable gels described byHubbell et al.(WO 93/17669) and Sawhney et al., (J. Biomed. Mats. Res.28, 831-838, 1994), systems for forming drug delivery depots or barrierson surfaces include the polymers described in U.S. Pat. No. 4,938,763 toDunn, et al., U.S. Pat. Nos. 5,100,992 and 4,826,945 to Cohn et al.,U.S. Pat. Nos. 4,741,872 and 5,160,745 to De Luca et al., and U.S. Pat.No. 4,511,478 to Nowinski et al. Use of preformed barrier materials suchas Goretex™ membrane (W. L. Gore) has been described in the literature.

Although all of these materials are suitable for application to tissueand other substrates, adhesion is in many cases limited, or in the caseof the preformed barrier materials, essentially non-existent.

There are many situations in which the application of a polymericmaterial, or a polymerizable material followed by polymerization, is theappropriate or preferred method of sealing a tissue or organ to preventmigration of a fluid, such as blood or air, from or into the tissue ororgan.

Well-known materials for making such bonds are cyanoacrylate-basedadhesives and fibrin glue. Cyanoacrylates are chemically related tofamiliar domestic adhesives such as “CrazyGlue™”. On contact with water,the cyanoacrylate residues spontaneously polymerize. The resultingresins are brittle, poorly biodegradable, and often not biocompatible.

Fibrin glues are typically made by contacting a solution or suspensionof the blood protein fibrinogen with an enzyme or other reagent whichcan crosslink it. Typically, the enzyme thrombin is used, which cleavesthe fibrinogen molecule, forming fibrin monomer which then spontaneouslypolymerizes. This is a natural reaction involved in the formation ofblood clots. Fibrin glues often have better adherence to tissues than docyanoacrylates, and are rapidly biodegraded. However, likecyanoacrylates, they have little flexibility or elasticity once theirdeposition is complete. A familiar example of a crosslinked fibrin-basedmaterial is a scab or an eschar.

Neither fibrin glues nor cyanoacrylates are stretchable, oncepolymerized. It is believed that this lack of compliance (i.e., highelastic modulus and low elongation at rupture) is an important reasonwhy seals formed with these and related prior-art materials are likelyto fail prematurely, especially when the area which is joined or sealedis subject to deformation.

Numerous materials are known and used in medicine which are highlyelastic, such as rubber gloves and flexible elastic bandages. However,such materials do not bind tightly to tissue, particularly to moist istissue, which is required if the tissue is to be sealed.

It is therefore an object of the present invention to provide methodsand compositions for enhancing the adhesion of polymeric materials totissue surfaces and other substrates.

It is a further object of the present invention to provide methods andcompositions for increasing the thicknesses of polymeric materials whichcan be “tethered” to a tissue surface or other substrates.

It is a further object of the present invention to provide improvedinitiator systems for the formation of gels on tissues and othersurfaces.

It is a further object of the present invention to provide improvedmethods and new medical indications for the sealing and coating oftissue.

It is another object of the invention to provide an improved sealingmaterial and method, characterized in that the sealant material iscompliant with tissue after its formation, as well as strongly adherentto tissue.

It is a further object of the invention to provide kits for theformation of such compliant sealant materials.

SUMMARY OF THE INVENTION

An improved barrier, coating or drug delivery system which is highlyadherent to the surface to which it is applied is disclosed, along withmethods for making the barrier. The barriers and coatings formed bypolymerization of polymerizable materials on the surface of tissue formbarriers or coatings which are compliant with the tissue, as well asadherent, i.e., are capable of conforming to the tissue. The polymerizedcoatings preferably are biocompatible and biodegradable.

In a preferred embodiment, tissue is stained with a photoinitiator, thenthe polymer solution or gel in combination with a defined amount of thesame or a different photoinitator is applied to the tissue. On exposureto light, the resulting system polymerizes at the surface, givingexcellent adherence, and also forms a gel throughout the illuminatedvolume. Thus a gel barrier or coating of arbitrary thickness can beapplied to a surface while maintaining high adherence at the interface.This process is referred to herein as “priming”. The polymerizablebarrier materials are highly useful for sealing tissue surfaces andjunctions against leaks of fluids. In the examples described below, thefluids are air and blood; however, the principle is also applicable toother fluids, including bowel contents, urine, bile, cerebrospinalfluid, vitreous and aqueous humors and other fluids whose migrationwithin a living organism must be contained.

In another embodiment, “priming” can be used to reliably adherepreformed barriers or coatings to tissue or other surfaces, or to adheretissue surfaces to each other. A first surface and a preformed barrieror coating, or another surface, are prestained with initiator, and athin layer of polymerizable monomer containing initiator is placedbetween them. Strong adhesion is obtained between the two surfaces onpolymerization of the monomer. In a similar fashion, tissue surfaces canbe adhered to each other in repair of wounds and formation ofanastomoses.

The priming method is suitable for any mode of polymerization. Whileespecially effective in photopolymerization, chemical or thermalpolymerization can also be accomplished by this method. Further, anenhancement of photoinitiation can be achieved by adding suitable redoxinitiation components to the system, providing a new form oflight-controlled chemically accelerated polymerization reaction,especially effective in the presence of blood.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the stress vs. strain curve of a compliant sealant formedby photopolymerization of a poly(ethylene glycol)-oligotrimethylenecarbonate copolymer end capped with acrylate ester.

DETAILED DESCRIPTION OF THE INVENTION

Materials with improved compliance, and methods for their manufactureand application to tissue are provided. In one embodiment, materials maybe used which are described in PCT/US/96/03834, filed Mar. 22, 1996, thedisclosure of which is incorporated herein by reference. Polymerizedbarriers or coatings may be formed from polymerizable precursormaterials which can include, for example, crosslinkable or curablemolecules. A wide variety of precursor materials may be used, providedthat they form cured or crosslinked materials having the properties ofbiocompatibility and an appropriate elastic property, such as acompliance ratio, as described in detail below. Preferably, thepolymerized materials are biodegradable. The compliant materials may beused as sealants, may contain biologically active materials, and be usedin drug delivery applications.

By selection of the appropriate polymerizable materials, polymericcompliant polymer coatings on tissue may be formed, and the propertiesof the polymers may be altered to control the normalized complianceratio of such polymers relative to that of a tissue.

Definitions

As used herein, the term “sealant” refers to a material which decreasesor prevents the migration of fluid from or into a surface such as atissue surface. Sealants are typically formed by the application ofprecursor molecules to a tissue followed by local polymerization. Thesame materials may also be used to adhere materials together, eitherwhen applied between them and polymerized, or when used to jointly embedmaterials.

As used herein, the term “biocompatibility,” in the context ofbiologically-related uses, refers to the absence of stimulation of asevere, long-lived or escalating biological response to an implant orcoating, and is distinguished from a mild, transient inflammation whichtypically accompanies surgery or implantation of foreign objects into aliving organism.

As used herein the term “biodegradability” refers to the disintegration,which is preferably predictable, of an implant into small entities whichwill be metabolized or excreted, under the conditions normally presentin a living tissue.

The properties of the particular coating or barrier materials disclosedherein are referred to as “materials properties”, and include:

the “Young's modulus” (of elasticity) which is the limiting modulus ofelasticity extrapolated to zero strain;

the “elastic modulus” which is any modulus of elasticity, not limited toYoung's modulus, and may include “secant modulus” and other descriptorsof non-linear regions of the stress-strain curve;

the “bulk” or “compressive” modulus which is used in its usual sense ofratio of stress to a designated compressive strain;

the “elongation at failure” which is the relative strain or extension ofa test specimen at which any irreversible or hysteresis-inducing changeoccurs in the specimen; and

the “elongation at break” or “elongation at rupture” which is therelative strain (extension) of a test specimen at which mechanicalrupture occurs.

The term “compliance” as used herein is used in a general sense, andrefers for example to the ability of an implant to closely match thephysiological and mechanical properties of tissues at the implant site,except when “compliance” is used in a specific technical sense as thereciprocal of a modulus.

As applied to a relatively thin, flat material such as a tissue or alayer of sealant, “normalized compliance” (NC) is defined herein as thestrain,(i.e., the elongation or compression per unit length of aspecimen), divided by the applied force per unit cross-sectional area,further divided by the thickness of the specimen. Hence, for a samplehaving a width w (for example, the width of the clamps of the testingapparatus), and a thickness t, when an applied force F produces a strainS, then the compliance C is$C = {\frac{S}{{F/w}\quad t} = \frac{{S \cdot w}\quad t}{F}}$

and the normalized compliance is${NC} = {\frac{C}{t} = {\frac{S}{F/w} = \frac{S\quad w}{F}}}$

i.e., the strain in the sample divided by the force per unit widthapplied to the sample. The normalized compliance allows directcomparison of the forces required to deform the tissue versus a coatingon the tissue, without regard to the relative thicknesses of thesematerials.

The normalized compliance ratio (abbreviated NCR) is defined as thevalue of the normalized compliance of the tissue or other substratedivided by the normalized compliance of the sealant material. When bothmeasurements are conducted on strips of the same width and at the sameforce, the NCR is simply the ratio of the strains at a particular force.A low NCR (less than 1) is obtained when the sealant material is easierto deform than the tissue, while a high NCR (greater than 1) is obtainedwhen the tissue is easier to deform than the sealing material.

As used herein, the term “elastomer” refers to a polymeric materialwhich at room temperature is capable of repeatedly recovering in sizeand shape after removal of a deforming force. In some embodiments, anelastomer is a material which can be repeatedly stretched to twice itsoriginal length and will repeatedly return to its approximate length onrelease of the stress.

The phrase “elastomeric materials” is a phrase which has been used inthe literature. There are many publications describingstructure-property relationships of elastomers and other deformablematerials. Lower elastic modulus and, frequently, an increasedreversible elongation to break or fracture, are found when any of thefollowing occur:

1. The distance between nodes or junctions or more crystalline (“hard”)segments increases.

2. The crosslink density decreases. This may be controlled by amount ofcrosslinker, nature of crosslinker, and degree of cure, as well as bysegment length of either the crosslinked species or the crosslinkingspecies, where different.

3. For a material at equilibrium with a continuous phase, an increase inthe plasticization of the elastomer by the continuous phase. Forapplications wherein the continuous phase is water, more particularlyphysiological saline, increasing hydrophilicity tends to increasecompliance.

In order to seal fluid leaks in tissue, the sealing material must remainfirmly bonded to the tissue during motions required of the tissue duringthe healing process. For tissues and organs which cannot be immobilized,such as the lung, an effective sealing material is both tightly-adherentand compliant, having materials properties similar to those of thetissue. Examples of compliant adherent materials and methods for theirconstruction and use are provided.

In one embodiment, one or more initiators are applied to a surface toform an absorbed layer. “Absorbed” is used herein to encompass both“absorbed” and “adsorbed”. A solution of polymerizable molecules,referred to herein as “monomers”, is then applied.

Methods

In one embodiment, one or more initiators or components of an initiationsystem are applied directly to the surface, and the unabsorbed excess isoptionally removed by washing or blotting. The initiator solution mayfurther contain one or more polymerizable monomers, and other usefulformulating ingredients, including accelerators, co-initiators,sensitizers, and co-monomers. Then a liquid containing polymerizablemonomers in combination with one or more initiators or components of aninitiation system, which may be the same as or different from thatabsorbed in the first step, is applied. The system, if notself-polymerizing, is then stimulated to polymerize, for example byapplication of an appropriate wavelength of light.

The priming and monomer-application steps can also be combined. Forexample, if excess initiator is not removed before monomer addition,then subsequent application of monomer will result in mixture ofinitiator into the monomer layer. Similarly, if the monomer layercontains an initiator with a high affinity for the surface, then it ispossible to apply a monomer layer containing initiator, and wait anappropriate time to allow preferential absorption of the initiator tothe surface, to achieve the same effect.

All of these methods may collectively be described as application of themonomer in an “initiating-incorporating manner”, encompassing any meansof application and mixing which results in both an absorbed layer ofinitiator, and a layer of monomer incorporating an initiator, beingpresent on a surface to be coated.

The initiators may be chemical, photochemical, or a combination thereof.With non-photochemical systems, a reductant component and an oxidantcomponent may be present in the two parts of the solution, i.e., in thepriming layer and the coating layer.

Alternatively, a two-step process can be used to form polymers,especially bioabsorbable hydrogels on tissue. In the first step thetissue is treated with an initiator or a part of an initiator system forthe polymerization of olefinic (e.g. acrylic) or other functionalmonomers, optionally with monomer in the priming solution. This providesan activated tissue surface. In the second step, monomer(s) and, ifappropriate, the remainder of an initiator system, are together placedin contact with the activated tissue, resulting in polymerization on thetissue. An example of such a system is the combination of a peroxygencompound in one part, and a reactive ion, such as a transition metal, inanother.

This process of spontaneous polymerization does not require the use of aseparate energy source. Moreover, since the process of polymerization isinitiated when part one contacts part two, there are no “pot life”issues due to initiation of polymerization. If desired, part one or parttwo can contain dyes or other means for visualizing the hydrogelcoating.

An example of a system that can be used in this method is thespontaneous “contact” initiator systems such as those found in two part“acrylic structural adhesives”. All components of the materials used asdescribed herein, however, must display biocompatibility as well as theability to spontaneously polymerize on tissue. The use of tributylborane for this purpose is illustrated here.

These systems can markedly simplify the delivery of gel to tissue,especially in areas hard to reach or hold for a photochemical system.The delivery system can be much simpler. Moreover, it has beendiscovered that a two-part chemical system such as a redox system andespecially one based on peroxygen, can be used to chemically enhance thecuring of a photochemical system, thereby combining the control of aphotochemical system with the ability of a chemical system to overcomecolored impurities, such as blood.

In one embodiment, as described in U.S. Pat. No. 5,410,016,biodegradable macromers are applied to tissue, followed byphotopolymerization to form a gel. In addition to the photopolymerizablegels described by Hubbell et al. (WO 93/17669) and Sawhney et al., (J.Biomed. Mats. Res., 28:831-838, 1994), systems for forming drug deliverydepots or barriers on surfaces include the polymers described in U.S.Pat. No. 4,938,763 to Dunn et al., U.S. Pat. Nos. 5,100,992 and4,826,945 to Cohn et al., U.S. Pat. Nos. 4,741,872 and 5,160,745 to DeLuca et al., U.S. Pat. No. 5,527,864 to Suggs et al., and U.S. Pat. No.4,511,478 to Nowinski et al. These materials, which covalentlycross-link by free-radical-initiated polymerization, are preferredmaterials. However, materials which cross-link by other mechanisms, orwhich comprise low-molecular weight reactive monomers, are alsopotentially suitable if they are biocompatible and non-toxic.

Compositions

Monomers

Any monomer capable of being polymerized to form a surface coating canbe used. The monomers may be small molecules, such as acrylic acid orvinyl acetate; or they may be larger molecules containing polymerizablegroups, such as acrylate-capped polyethylene glycol (PEG-diacrylate), orother polymers containing ethylenically-unsaturated groups, such asthose of U.S. Pat. No 4,938,763 to Dunn et al., U.S. Pat. Nos. 5,100,992and 4,826,945 to Cohn et al., U.S. Pat. Nos. 4,741,872 and 5,160,745 toDe Luca et al., or U.S. Pat. No. 5,410,016 by Hubbell et al. Propertiesof the monomer, other than polymerizability, will be selected accordingto the use, using principles as known in the art. There is an extensiveliterature on the formulation of polymerizable coating materials forparticular applications; these formulae can readily be adapted to usethe improved adherence-promoting polymerization system described hereinwith little experimentation.

In the particular application area of coating of tissues, cells, medicaldevices, and capsules, formation of implants for drug delivery or asmechanical barriers or supports, and other biologically related uses,the general requirement of the coating materials are biocompatibilityand lack of toxicity. For all biologically-related uses, toxicity mustbe low or absent in the finished state for externally coated non-livingmaterials, and at all stages for internally-applied materials.Biocompatibility, in the context of biologically-related uses, is theabsence of stimulation of a severe, long-lived or escalating biologicalresponse to an implant or coating, and is distinguished from a mild,transient inflammation which accompanies implantation of essentially allforeign objects into a living organism.

The monomer solutions should not contain harmful or toxic solvents.Preferably, the monomers are substantially soluble in water to allowtheir application in a physiologically-compatible solution, such asbuffered isotonic saline. Water-soluble coatings may form thin films,but more preferably form three-dimensional gels of controlled thickness.

It is especially preferable in cases involving implants that the coatingformed be biodegradable, so that it does not have to be retrieved fromthe body. Biodegradability, in this context, is the predictabledisintegration of an implant into small molecules which will bemetabolized or excreted, under the conditions normally present in aliving tissue.

The macro-monomers (“macromers”) which are covalently crosslinkable toform hydrogels preferably comprise a block copolymer. The macromers canbe quickly polymerized from aqueous solutions. The macromers mayadvantageously be capable of thermoreversible gelation behavior, and maybe polymerized from a solution state or from a gel state.

Preferred monomers are the photopolymerizable, biodegradable,water-soluble macromers described by Hubbell et al. in U.S. Ser. No.08/022,687, the teachings of which are incorporated herein. Thesemonomers are characterized by having at least two polymerizable groups,separated by at least one degradable region. When polymerized in water,they form coherent gels which persist until eliminated byself-degradation. In the most preferred embodiment, the macromer isformed with a core of a polymer which is water soluble andbiocompatible, such as the polyalkylene oxide polyethylene glycol,flanked by hydroxy acids such as lactic acid, having coupled theretoacrylate groups. Preferred monomers, in addition to being biodegradable,biocompatible, and non-toxic, will also be at least somewhat elasticafter polymerization or curing. Elasticity, or repeatablestretchability, is often exhibited by polymers with low modulus. Brittlepolymers, including those formed by polymerization of cyanoacrylates,are not generally effective in contact with biological soft tissue.

It has been determined that monomers with longer distances betweencrosslinks are generally softer, more compliant, and more elastic. Thus,in the polymers of Hubbell, et al., increased length of thewater-soluble segment, such as polyethylene glycol, tends to give moreelastic gel, and these tend to adhere better, especially understretching (as when applied to lung). Molecular weights in the range of10,000 to 35,000 of polyethylene glycol are preferred for suchapplications, although ranges from 3,000 to 100,000 are useful.

In the discussion below and the examples, monomers of this kind, alsocalled macromers, are often designated by a code of the form xxKZn.“xxK” represents the molecular weight of the backbone polymer, which ispolyethylene glycol unless otherwise stated, in thousands of daltons. Zdesignates the biodegradable linkage, where L is for lactic acid, G isfor glycolic acid, C is for caprolactone, and TMC is fortrimethylenecarbonate. N is the average number of degradable groups inthe block. The molecules are terminated with acrylic acid groups, unlessotherwise stated; this is sometimes also indicated by the suffix A2.

Crosslinkable Groups

The monomers or macromers preferably include crosslinkable groups whichare capable of forming covalent bonds with other compounds while inaqueous solution. These crosslinkable groups permit crosslinking of themacromers to form a gel, either after, or independently from thermallydependent gelation of the macromer. Chemically or ionicallycrosslinkable groups known in the art may be provided in the macromers.The crosslinkable groups in one preferred embodiment are polymerizableby photoinitiation by free radical generation, most preferably in thevisible or long wavelength ultraviolet radiation. The preferredcrosslinkable groups are unsaturated groups including vinyl groups,allyl groups, cinnamates, acrylates, diacrylates, oligoacrylates,methacrylates, dimethacrylates, oligomethoacrylates, or otherbiologically acceptable photopolymerizable groups.

Other polymerization chemistries which may be used include, for example,reaction of amines or alcohols with isocyanate or isothiocyanate, or ofamines or thiols with aldehydes, epoxides, oxiranes, or cyclic imines;where either the amine or thiol, or the other reactant, or both, may becovalently attached to a macromer. Mixtures of covalent polymerizationsystems are also contemplated. Sulfonic acid or carboxylic acid groupsmay be used.

Preferably, at least a portion of the macromers will be crosslinkers,i.e., will have more than one crosslinkable reactive group, to permitformation of a coherent hydrogel by ensuring the crosslinking of thepolymerized macromers. Up to 100% of the macromers may have more thanone reactive group. Typically, in a synthesis, the percentage will be onthe order of 50 to 95%, for example, 60 to 80%. The percentage may bereduced by addition of co-monomers containing only one active group. Alower limit for crosslinker concentration will depend on the propertiesof the particular macromer and the total macromer concentration, butwill be at least about 3% of the total molar concentration of reactivegroups. More preferably, the crosslinker concentration will be at least10%, with higher concentrations, such as 30% to 90%, being optimal formaximum retardation of diffusion of many drugs. Optionally, at leastpart of the crosslinking function may be provided by a low-molecularweight crosslinker. When the drug to be delivered is a macromolecule,higher ranges of polyvalent macromers (i.e., having more than onereactive group) are preferred. If the gel is to be biodegradable, as ispreferred in most applications, then the crosslinking reactive groupsshould be separated from each other by biodegradable links. Any linkageknown to be biodegradable under in vivo conditions may be suitable, suchas a degradable polymer block. The use of ethylenically unsaturatedgroups, crosslinked by free radical polymerization with chemical and/orphotoactive initiators, is preferred as the crosslinkable group.

The macromer may also include an ionically charged moiety covalentlyattached to a macromer; which optionally permits gelation or ioniccrosslinking of the macromer.

Hydrophilic Regions

Water soluble hydrophilic oligomers available in the art may beincorporated into the biodegradable macromers. The hydrophilic regioncan be for example, polymer blocks of poly(ethylene glycol),poly(ethylene oxide), poly(vinyl alcohol), poly(vinylpyrrolidone),poly(ethyloxazoline), or polysaccharides or carbohydrates such ashyaluronic acid, dextran, heparan sulfate, chondritin sulfate, heparin,or alginate, or proteins such as gelatin, collagen, albumin, ovalbumin,or polyamino acids.

Biodegradable Regions

Biodegradable molecules or polymers thereof available in the art may beincorporated into the macromers. The biodegradable region is preferablyhydrolysable under in vivo conditions. In some embodiments, thedifferent properties, such as biodegradability and hydrophobicity orhydrophilicity, may be present within the same region of the macromer.

Useful hydrolyzable groups include polymers and oligomers of glycolide,lactide, epsilon-caprolactone, other hydroxy acids, and otherbiologically degradable polymers that yield materials that are non-toxicor present as normal metabolites in the body. Preferredpoly(alpha-hydroxy acids) are poly(glycolic acid), poly(DL-lactic acid)and poly(L-lactic acid). Other useful materials include poly(aminoacids), polycarbonates, poly(anhydrides), poly(orthoesters),poly(phosphazines) and poly(phosphoesters). Polylactones such aspoly(epsilon-caprolactone), poly(delta-caprolactone),poly(delta-valerolactone) and poly(gamma-butyrolactone), for example,are also useful. The biodegradable regions may have a degree ofpolymerization ranging from one up to values that would yield a productthat was not substantially water soluble. Thus, monomeric, dimeric,trimeric, oligomeric, and polymeric regions may be used.

Biodegradable regions can be constructed from polymers or monomers usinglinkages susceptible to biodegradation, such as ester, peptide,anhydride, orthoester, phosphazine and phosphoester bonds. The timerequired for a polymer to degrade can be tailored by selectingappropriate monomers. Differences in crystallinity also alterdegradation rates. For relatively crystalline or hydrophobic polymers,actual mass loss may only begin when the oligomeric fragments are smallenough to be water soluble. Thus, initial polymer molecular weight andstructure will influence the degradation rate.

Initiators

The term “initiator” is used herein in a broad sense, in that it is acomposition which under appropriate conditions will result in thepolymerization of a monomer. Materials for initiation may bephotoinitiators, chemical initiators, thermal initiators,photosensitizers, co-catalysts, chain transfer agents, and radicaltransfer agents. All initiators known in the art are potentiallysuitable for the practice of the priming technique. The criticalproperty of an initiator is that the polymerization will not proceed ata useful rate without the presence of the initiator.

The “priming” initiator must adhere sufficiently to the surface to becoated to provide a local source of initiation of the reaction with theparticular monomers to be applied. The initiator must also not be toxicwhen used in biologically-related applications, at least in the amountsapplied. The initiator is preferably a photoinitiator. In discussingphotoinitiators, a distinction may be drawn between photosensitizers andphotoinitiators—the former absorb radiation efficiently, but do notinitiate polymerization well unless the excitation is transferred to aneffective initiator or carrier. Photoinitiators as referred to hereininclude both photosensitizers and photoinitiators, unless otherwisenoted.

Photoinitiators provide important curing mechanisms for additionpolymerization, and especially for curing of ethylenically-unsaturatedcompounds, such as vinylic and acrylic-based monomers. Any of thephotoinitiators found in the art may be suitable, if they adhere to theparticular surface. Examples of photo-oxidizable and photo-reducibledyes that may be used to initiate polymerization include acridine dyes,for example, acriblarine; thiazine dyes, for example, thionine; xanthinedyes, for example, rose Bengal; and phenazine dyes, for example,methylene blue. Other initiators include camphorquinones andacetophenone derivatives. Photoinitiation is a preferred method ofpolymerizing the coatings and adhesives.

The choice of the photoinitiator is largely dependent on thephotopolymerizable regions. For example, when the macromer includes atleast one carbon-carbon double bond, light absorption by the dye causesthe dye to assume a triplet state, the triplet state subsequentlyreacting with the amine to form a free radical which initiatespolymerization. In an alternative mechanism, the initiator splits intoradical-bearing fragments which initiate the reaction. Preferred dyesfor use with these materials include eosin dye and initiators such as2,2-dimethyl-2-phenylacetophenone, 2-methoxy-2-phenylacetophenone,Darocur™ 2959, Irgacure™ 651 and camphorquinone, Using such initiators,copolymers may be polymerized in situ by long wavelength ultravioletlight or by light of about 514 nm, for example.

A preferred photoinitiator for biological use is Eosin Y, which absorbsstrongly to most tissue and is an efficient photoinitiator.

It is known in the art of photopolymerization to use a wavelength oflight which is appropriate for the activation of a particular initiator.Light sources of particular wavelengths or bands are well-known.

Thermal polymerization initiator systems may also be used. Systems thatare unstable at 37° C. and initiate free radical polymerization atphysiological temperatures include, for example, potassium persulfate,with or without tetramethyl ethylenediamine; benzoyl peroxide, with orwithout triethanolamine; and ammonium persulfate with sodium bisulfite.Other peroxygen compounds include t-butyl peroxide, hydrogen peroxideand cumene peroxide. As described below, it is possible to markedlyaccelerate the rate of a redox polymerization by including metal ions inthe solution, especially transition metal ions such as the ferrous ion.It is further shown below, that a catalysed redox reaction can beprepared so that the redox-catalysed polymerization is very slow, butcan be speeded up dramatically by stimulation of a photoinitiatorpresent in the solution.

A further class of initiators is provided by compounds sensitive towater, which form radicals in its presence. An example of such amaterial is tri-n-butyl borane, the use of which is described below

Redox Initiators

Metal ions can be either an oxidizer or a reductant in systems includingredox initiators For example, in some examples below, ferrous ion isused in combination with a peroxide to initiate polymerization, or asparts of a polymerization system. In this case the ferrous ion isserving as reductant. Other systems are known in which a metal ion actsas oxidant. For example, the ceric ion (4+ valence state of cerium) caninteract with various organic groups, including carboxylic acids andurethanes, to remove an electron to the metal ion, and leaving aninitiating radical behind on the organic group. Here the metal ion actsas an oxidizer. Potentially suitable metal ions for either role are anyof the transition metal ions, lanthanides and actinides, which have atleast two readily accessible oxidation states. Preferred metal ions haveat least two states separated by only one difference in charge. Ofthese, the most commonly used are ferric/ferrous; cupric/cuprous;ceric/cerous; cobaltic/cobaltous; vanadate V vs. IV; permanganate; andmanganic/manganous.

Co-initiators and Comonomers

Any of the compounds typically used in the art as radical generators orco-initiators in photoinitiation may be used. These include co-catalystsor co-initiators such as amines, for example, triethanolamine, as wellas other trialkyl amines and trialkylol amines; sulfur compounds;heterocycles, for example, imidazole; enolates; organometallics; andother compounds, such as N-phenyl glycine.

Co-monomers can also be used. They are especially useful when themonomer is a macromolecule, as in Example 1 below; in that case, any ofthe smaller acrylate, vinyl or allyl compounds can be used. Comonomerscan also act as accelerators of the reaction, by their greater mobility,or by stabilizing radicals. Of particular interest are N-vinylcompounds, including N-vinyl pyrrolidone, N-vinyl acetamide, N-vinylimidazole, N-vinyl caprolactam, and N-vinyl formamide.

Surfactants, Stabilizer, and Plasticizers

Other compounds can be added to the initiator and/or monomer solutions.Surfactants may be included to stabilize any of the materials, eitherduring storage or in a form reconstituted for application. Similarly,stabilizers which prevent premature polymerization may be included;typically, these are quinones, hydroquinones, or hindered phenols.Plasticizers may be included to control the mechanical properties of thefinal coatings. These are also well-known in the art, and include smallmolecules such as glycols and glycerol, and macromolecules such aspolyethylene glycol.

Surfaces to be Treated

Surfaces to be coated include biologically-related surfaces of allkinds, and include the surface of drug delivery devices such ascatheters or prosthetic implants. Any tissue or cell surface iscontemplated, as well as the surface of a device to be used in the bodyor in contact with bodily fluids. A coating may be applied to thesurface of any of these, in an amount effective to improve tenacity ofadherence. Moreover, the technique may be used to adhere surfaces toeach other For example, wounds in living tissue may be bonded or sealedusing this technique or preformed medical appliances may be bonded totissue. Examples of such applications are grafts, such as vasculargrafts; implants, such as heart valves, pacemakers, artificial corneas,and bone reinforcements; supporting materials, such as meshes used toseal or reconstruct openings; and other tissue-non-tissue interfaces. Aparticularly important class of tissue surfaces is those which arefriable, and therefore will not support sutures well. Adherent coatingscan seal the suture lines, support sutured areas against mechanicalstress, or substitute entirely for sutures when-mechanical stress islow. Examples of such situations include vascular anastomosis, nerverepair, repair of the cornea or the cochlea, and repair of the lung,liver, kidney and spleen.

The priming technique can also be used on non-tissue surfaces ingeneral, where useful bonds may be formed between similar or dissimilarsubstances, and solid or gel coatings are tightly adhered to surfaces.In particular, a pre-formed gel, or other fragile material, may betightly adhered to a supporting material by this method.

The priming method is advantageous because it can be used to coat and orto bond together any of a wide variety of surfaces. These include allsurfaces of the living body, and surfaces of medical devices, implants,wound dressings and other body-contacting artificial or naturalsurfaces. These include, but are not limited to, at least one surfaceselected from the following: a surface of the respiratory tract, themeninges, the synovial spaces of the body, the peritoneum, thepericardium, the synovia of the tendons and joints, the renal capsuleand other serosae, the dermis and epidermis, the site of an anastomosis,a suture, a staple, a puncture, an incision, a laceration, or anapposition of tissue, a ureter or urethra, a bowel, the esophagus, thepatella, a tendon or ligament, bone or cartilage, the stomach, the bileduct, the bladder, arteries and veins; and devices such as percutaneouscatheters (e.g. central venous catheters), percutaneous cannulae (e.g.for ventricular assist devices), urinary catheters, percutaneouselectrical wires, ostomy appliances, electrodes (surface and implanted),and implants including pacemakers, defibrillators, and tissueaugmentations.

Biologically Active Agents

Biologically active materials may be included in any of the coatingsdescribed herein, as ancillaries to a medical treatment (for example,antibiotics) or as the primary objective of a treatment (for example, agene to be locally delivered). A variety of biologically activematerials may be included, including passively-functioning materialssuch as hyaluronic acid, as well as active agents such as growthhormones. All of the common chemical classes of such agents areincluded: proteins (including enzymes, growth factors, hormones andantibodies), peptides, organic synthetic molecules, inorganic compounds,natural extracts, nucleic acids (including genes, antisense nucleotides,ribozymes and triplex forming agents), lipids and steroids,carbohydrates (including heparin), glycoproteins, and combinationsthereof.

The agents to be incorporated can have a variety of biologicalactivities, such as vasoactive agents, neuroactive agents, hormones,anticoagulants, immunomodulating agents, cytotoxic agents, antibiotics,antivirals, or may have specific binding properties such as antisensenucleic acids, antigens, antibodies, antibody fragments or a receptor.Proteins including antibodies or antigens can also be delivered.Proteins are defined as consisting of 100 amino acid residues or more;peptides are less than 100 amino acid residues. Unless otherwise stated,the term protein refers to both proteins and peptides. Examples includeinsulin and other hormones.

Specific materials include antibiotics, antivirals, antiinflammatories,both steroidal and non-steroidal, antineoplastics, anti-spasmodicsincluding channel blockers, modulators of cell-extracellular matrixinteractions including cell growth inhibitors and anti-adhesionmolecules, enzymes and enzyme inhibitors, anticoagulants and/orantithrombotic agents, growth factors, DNA, RNA, inhibitors of DNA, RNAor protein synthesis, compounds modulating cell migration, proliferationand/or growth, vasodilating agents, and other drugs commonly used forthe treatment of injury to tissue. Specific examples of these compoundsinclude angiotensin converting enzyme inhibitors, prostacyclin, heparin,salicylates, nitrates, calcium channel blocking drugs, streptokinase,urokinase, tissue plasminogen activator (TPA) and anisoylatedplasminogen activator (TPA) and anisoylated plasminogen-streptokinaseactivator complex (APSAC), colchicine and alkylating agents, andaptomers. Specific examples of modulators of cell interactions includeinterleukins, platelet derived growth factor, acidic and basicfibroblast growth factor (FGF), transformation growth factor β (TGF β),epidermal growth factor (EGF), insulin-like growth factor, andantibodies thereto. Specific examples of nucleic acids include genes andcDNAs encoding proteins, expression vectors, antisense and otheroligonucleotides such as ribozymes which can be used to regulate orprevent gene expression. Specific examples of other bioactive agentsinclude modified extracellular matrix components or their receptors, andlipid and cholesterol sequestrants.

Examples of proteins further include cytokines such as interferons andinterleukins, poetins, and colony-stimulating factors. Carbohydratesinclude Sialyl Lewis^(x) which has been shown to bind to receptors forselectins to inhibit inflammation. A “Deliverable growth factorequivalent” (abbreviated DGFE), a growth factor for a cell or tissue,may be used, which is broadly construed as including growth factors,cytokines, interferons, interleukins, proteins, colony-stimulatingfactors, gibberellins, auxins, and vitamins; further including peptidefragments or other active fragments of the above; and further includingvectors, i.e., nucleic acid constructs capable of synthesizing suchfactors in the target cells, whether by transformation or transientexpression; and further including effectors which stimulate or depressthe synthesis of such factors in the tissue, including natural signalmolecules, antisense and triplex nucleic acids, and the like. ExemplaryDGFE's are vascular endothelial growth factor (VEGF), endothelial cellgrowth factor (ECGF), basic fibroblast growth factor (bFGF), bonemorphogenetic protein (BMP), and platelet derived growth factor (PDGF),and DNA's encoding for them Exemplary clot dissolving agents are tissueplasminogen activator, streptokinase, urokinase and heparin.

Drugs having antioxidant activity (i.e., destroying or preventingformation of active oxygen) may be used, which are useful, for example,in the prevention of adhesions. Examples include superoxide dismutase,or other protein drugs include catalases, peroxidases and generaloxidases or oxidative enzymes such as cytochrome P450, glutathioneperoxidase, and other native or denatured hemoproteins.

Mammalian stress response proteins or heat shock proteins, such as heatshock protein 70 (hsp 70) and hsp 90, or those stimuli which act toinhibit or reduce stress response proteins or heat shock proteinexpression, for example, flavonoids, also may be used.

The macromers may be provided in pharmaceutical acceptable carriersknown to those skilled in the art, such as saline or phosphate bufferedsaline. For example, suitable carriers for parenteral adminstration maybe used.

Methods of Treatment

Generally, any medical condition which requires a coating or sealinglayer may be treated by the methods described herein to produce acoating with better adherence. For example, lung tissue may be sealedagainst air leakage after surgery using the priming technique. Likewise,wounds may be closed; leakage of blood, serum, urine, cerebrospinalfluid, air, mucus, tears, bowel contents or other bodily fluids may bestopped or minimized; barriers may be applied to prevent post-surgicaladhesions, including those of the pelvis and abdomen, pericardium,spinal cord and dura, tendon and tendon sheath. The technique may alsobe useful for treating exposed skin, in the repair or healing ofincisions, abrasions, burns, inflammation, and other conditionsrequiring application of a coating to the outer surfaces of the body.The technique is also useful for applying coatings to other bodysurfaces, such as the interior or exterior of hollow organs, includingblood vessels. In particular, restenosis of blood vessels or otherpassages can be treated. The techniques can also be used for attachingcell-containing matrices, or cells, to tissues, such as meniscus orcartilage.

General Sealing of Biological Tissues

As shown in the examples below, the priming method of polymerization isespecially effective in the sealing of biological tissues to preventleakage. However, the examples also demonstrate that a degree of sealingcan be achieved with photopolymerizable systems without the improvementof priming the tissue with photopolymerizing initiator. There have beennumerous attempts to reliably seal tissue with a number of materials,including most prominently cyanoacrylates and fibrin glues. None ofthese prior art techniques has been entirely satisfactory.Cyanoacrylates, which polymerize on exposure to moisture, and can beaccelerated by amines, are very “stiff” once polymerized. If there isany motion of the biological material, they tend to crack, and losetheir self-cohesion and/or their adherence to tissue. Fibrin glues canbe difficult to prepare, especially in the currently-preferredautologous version; they require enzymatic or toxic chemical means to begelled or crosslinked; and they are rapidly degraded by native enzymes.

The range of uses of sealing or bonding materials in the body is verylarge, and encompasses many millions of potential uses each year. Incardiovascular surgery, uses for tissue sealants include bleeding from avascular suture line; support of vascular graft attachment; enhancingpreclotting of porous vascular grafts; stanching of diffuse nonspecificbleeding; anastomoses of cardiac arteries, especially in bypass surgery;support of heart valve replacement; sealing of patches to correct septaldefects; bleeding after sternotomy; and arterial plugging. Collectively,these procedures are performed at a rate of 1 to 2 million annually.

In other thoracic surgery, uses include sealing of bronchopleuralfistulas, reduction of mediastinal bleeding, sealing of esophagealanastomoses, and sealing of pulmonary staple or suture lines. Inneurosurgery, uses include dural repairs, microvascular surgery, andperipheral nerve repair. In general surgery, uses include bowelanastomoses, liver resection, biliary duct repair, pancreatic surgery,lymph node resection, reduction of seroma and hematoma formation,endoscopy-induced bleeding, plugging or sealing of trocar incisions, andrepair in general trauma, especially in emergency procedures.

In plastic surgery, uses include skin grafts, burns, debridement ofeschars, and blepharoplasties (eyelid repair). In otorhinolaryngology(ENT), uses include nasal packing, ossicular chain reconstruction, vocalcord reconstruction and nasal repair. In opthalmology, uses includecorneal laceration or ulceration, and retinal detachment. In orthopedicsurgery, uses include tendon repair, bone repair, including filling ofdefects, and meniscus repairs. In gynecology/obstetrics, uses includetreatment of myotomies, repair following adhesiolysis, and prevention ofadhesions. In urology, sealing and repair of damaged ducts, andtreatment after partial nephrectomy are potential uses. Sealing can alsobe of use in stopping diffuse bleeding in any of a variety ofsituations, including especially treatment of hemophiliacs. In dentalsurgery, uses include treatment of periodontal disease and repair aftertooth extraction. Repair of incisions made for laparoscopy or otherendoscopic procedures, and of other openings made for surgical purposes,are other uses. Additional uses include separation of tissues to preventdamage by rugging during healing. Similar uses can be made in veterinaryprocedures. In each case, appropriate biologically active components maybe included in the sealing or bonding materials.

Application Techniques and Devices

Both priming and polymer addition may be accomplished by simple drippingof material onto the surface to be coated. This can be accomplishedusing common devices such as a syringe, a pipet, or a hose, depending onscale. More uniform applications may be obtained using an applicator,such as a brush, a pad, a sponge, a cloth, or a spreading device such asa finger, a coating blade, a balloon, or a skimming device. These mayfurther be used to rub the surface to improve penetration of the primeror the monomer, or to mix primer and monomer in situ on the surface. Inlarge-scale applications, fluid layers may be applied with large-scalecoating machinery, including roll coaters, curtain coaters, gravure andreverse gravure devices, and any of the coating devices known in theart. Sprayers may be used at any scale, especially for lower-viscosityprimers or polymerizable monomer layers.

Application techniques and devices may be combined, as in applying fluidfrom a syringe, and then rubbing it into the surface with a finger tip.Such operations may be repeated, as in applying drops of priminginitiator; rubbing these into the surface with-a brush; repeating thisoperation; adding monomer solution; rubbing it in; and finally applyingadditional layers of monomer before or during the application of curingmeans, such as light, heat, or slow release of peroxide radicals.

An additional application means which is required in many coatingtechniques described herein, and in particular in the preferred coatingmethod which uses photoinitiation to cure the monomer, is a lightsource. For large-scale application, flood lamps and similar devices areuseful. In small, localized applications, such as tissue sealing andcoating, it may be preferable to use a localized source such as a fiberoptic or light guide, which can project radiation of the appropriatewavelength onto the site to be treated to cause polymerization of themonomer. Also, a light emitter could be carried on a device, as aminiature bulb. A focused beam from a remote source could be suitableif, for example, the surface was exposed. In exposed surfaces, it ispossible that ambient light could be sufficient to polymerize thecoating, especially at high initiator levels.

Each of the applications means can be separate, so that a kit ofapplication means could contain, for example, one or more containers orreservoirs, one or more pads or brushes, and if required at least onelight guide. The application means could also be combined in whole or inpart. For example, a dripping device, such as a tube, could be combinedwith a spreading device, such as a brush. These could further becombined with a light guide. Such combination devices are especiallydesirable in treatment of living organisms, and especially humans, tomaximize the simplicity of a procedure and the probability of correctlyconducting it.

Compliance Properties

The compliance properties of the material herein described are those ofthe material after it has polymerized to form a polymerized material. Asused herein, “polymerized material” includes material which forms by theionic or covalent reaction of monomer precurser molecules. Preferably,the polymerized material is formed by covalent reactions of themonomers. It can be very difficult to measure the elastic properties ofthe material when adhered to tissue. The mechanical properties aretherefore when appropriate measured on samples made in vitro, either ina mold, or, as in the lap-shear test, in contact with standardizedtissue. Such measurements must be corrected to conditions applicable totissue treatment, including the diluting effects of polymerizationreagents, or of fluids on the tissue Thus, a sealing solution may beapplied to tissue at a concentration of 30%, but in the coating processit may be diluted to 15% effective concentration by dilution with bloodor plasma. Similarly, especially in the case of fibrin sealant, thepolymer concentration may be reduced by mixing with polymerizingreagents, either in bulk or by spraying. Where appropriate, suchcorrections have been taken into account in the descriptions herein.Materials may be equilibrated with water before testing either byabsorption or syneresis.

In light of these observations, an effective material for forming acompliant coating or sealant preferably has a strain or elongationbefore fracture substantially similar to or at least as great as theexpected strain during normal use of the tissue to which it is applied,and the elongation of the polymerized material is preferably reversible.This is to avoid either detachment from the tissue or fracture, orlimitation of the tissue's natural expansion. Preferably, the effectivecompliant material will have a reversible elongation at least about 150%as great, more preferably at least about 200% as great, and still morepreferably at least about 300% as great as the expected strain of thetissue.

The polymerized material thus may be designed and selected forapplication to different tissue, to have an elongation at rupture whichis similar to or greater than the elongation of the tissue in vivoduring its function. The elongation at rupture of the polymerizedmaterial can be, for example, greater than 100% or 200%, or optionallygreater than 300% or 400%. In some embodiments, the elongation atrupture of the polymerized material may be between for example 100% and700%, depending on the tissue properties In some applications, anelongation at rupture greater than 700% is useful.

In addition, the compliant material, for example in sealantapplications, preferably should have a normalized compliance that iscomparable in magnitude to the normalized compliance of the tissue towhich it is applied. The material will be operative even when thematerial's normalized compliance is much greater than the normalizedcompliance of the tissue.

In cases where minimal modification of the natural expansion andcontraction of a tissue is desired, the preferred range of thenormalized compliance ratio extends from about 0.05 to about 3,preferably from about 0.1 to about 2.0, and more preferably from about0.1 to about 1.0. In some cases, for example when the tissue is lungtissue, a value of the elastic modulus of less than about 150 kPa,preferably less than 100 kPa, more preferably less than about 50 kPa,and most preferably less than about 30 kPa is preferred.

To obtain the desired ratio of the normalized compliance of thepolymerized material to the normalized compliance of tissue, the overallforce required to stretch the sealant layer should be adjusted, sincethat of the tissue is fixed. The adjustment can be accomplished by anyof several known methods, including the alteration of the thickness ofthe layer of the polymerized material, or the variation of the polymerconcentration, or of the polymer crosslink density, or of otherproperties of the material. The properties of the precursor materialsand the reaction conditions may be adjusted to produce desired otherproperties of the polymerized material, such as sealant or adhesiveproperties, or controlled degradation and drug release properties

Where prevention of tissue deformation is desired, for example during ahealing period, the parameters of the tissue coating can be adjusted sothat the normalized compliance ratio is significantly in excess of 1.

The adherence of the polymerized material to the tissue is important inorder to obtain the benefits of proper compliance properties. Anadherence of at least about 20 gm/cm² in a single or double lap sheartest is preferable for many applications. Use of priming technology,described elsewhere in this application, is an effective method forobtaining such values. In some applications, such as the use of thepolymerized material as a tissue sealant, adherence values of about 30gm/cm² are preferred, and values at or above 40 gm/cm² are morepreferred.

In many applications, such as tissue sealing, the viscosity of theprecursor materials can be tailored to obtain optimal coatings. Higherviscosities can favor retention of the uncured or unpolymerized sealantat the site of application, and minimize displacement of the sealant bythe presence of bodily fluids at the surface. However, higherviscosities make the material more difficult to apply. A suitable rangeof viscosity, for example, for the sealant portion of a sealing systemis in the range of about 200 cP (centipoise) to about 40,000, preferablyabout 500 to about 5000 cP, and more preferably about 700 to about 1200cP. For lung, a suitable range of viscosity is about 900 to 1000 cP Theoptimal viscosity will depend on the site of application and the natureof the condition which is to be alleviated by the application of thematerial.

Packaging

The materials for making the coating can be packaged in any convenientway, and may form a kit including for example separate containers, aloneor together with the application device. The reactive monomers arepreferably stored separately from the initiator, unless they areco-lyophilized and stored in the dark, or otherwise maintainedunreactive. A convenient way to package the materials is in three vials(or prefilled syringes), one of which contains concentrated initiatorfor priming, the second of which contains reconstitution fluid, and thethird containing dry or lyophilized monomer. Dilute initiator is in thereconstitution fluid; stabilizers are in the monomer vial; and otheringredients may be in either vial, depending on chemical compatibility.If a drug is to be delivered in the coating, it may be in any of thevials, or in a separate container, depending on its stability andstorage requirements.

It is also possible, for a more “manual” system, to package some or allof the chemical ingredients in pressurized spray cans for rapiddelivery. If the monomer is of low enough viscosity, it can be deliveredby this route. A kit might then contain a spray can of initiator; aspray can or dropper bottle of monomer, initiator and other ingredients;and an optional spreading or rubbing device. If the monomer andinitiator system are designed to polymerize under the influence ofnatural or operating room light, possibly with the supplement of achemical initiator or carrier such as a peroxygen compound, then thetechnique could be suitable for field hospital or veterinary situations.

The present invention will be further understood by reference to thefollowing non-limiting examples.

EXAMPLE 1 Relative Adhesion of Coating to Primed and Unprimed Surfaces

Fresh pig lung was primed in one area with a solution of photoinitiator(Eosin Y, 1 mg/mL (1000 ppm) in normal saline) and in another area withnormal saline (prior art control). Excess fluid was removed by blotting.About 0.5 mL of monomer solution was applied to each spot. The monomerwas polyethylene glycol (35,000 Daltons) terminated with caprolactone(average of 3.3 caprolactone groups per polyethylene glycol molecule)and capped with acrylic acid, essentially as described in Hubbell et al.The monomer solution contained 15% monomer (w/w), 90 mM triethanolamine,20 ppm (w/w) Eosin Y, and 5 microliters/mL vinylpyrrolidone (v/v). Thesamples were irradiated with green light until cured (40 sec. at 100mW/cm²) into a firm, transparent gel. Initial adherence was seen in bothprimed and control spots, although the primed spots had better overalladherence.

The lung was connected to a pressure-controlled inflation apparatus, andsubjected to chronic fatigue for 1 hour of pneumatic inflation pressuresat 25 to 30 cm of water, in 6 second cycles. This was designed tosimulate the effects of breathing. After the fatigue test, the primedgel spots were still adherent, but the control gel spots could easily belifted from the lung surface with forceps. Thus, adhesion under chronicstress was better with priming before polymerization.

EXAMPLE 2 Sealing of Wedge Resection of Lung

In lung operations, it is common to make a “wedge resection” to removediseased areas. A combination stapler/cutter is used to simultaneouslycut and staple along one side of the wedge to be removed, and is thenused to staple and cut the other side so that a wedge-shaped piece oflung is removed, while the remaining lung is simultaneously stapledclosed. Despite a high staple density, the staple lines are prone toleak air, which can produce severe complications in a patient undergoingsuch an operation.

Frozen-thawed pig lungs were wedge-resectioned, using a ProxiMate™ TLC55 reloadable linear cutter/stapler (Ethicon; Somerville, N.J.). Everysecond staple was omitted from the outer staple lines in the cassette toreliably induce leaks. Lungs were inflated with air to a pressure of 40cm H₂O, and leaks were observed by pushing the stapled area just underthe surface of a water bath (similar to leak testing of an inner tube).Next, staple lines were primed with 1000 ppm Eosin Y, blotted, andtreated with the macromer mixture of Example 1 which was then cured asdescribed.

In a standard test for durability, the lungs were inflated to 20 cmwater pressure for 10 cycles, over a period of 1 minute; and then heldfor 30 seconds at 40 cm water. The primed and sealed lung sectionsshowed no leaks, demonstrating the effectiveness of the priming systemin sealing known leaks.

Finally, pressure was increased in the primed lungs to determine themaximum pressure before leakage. Small leaks were typically seen at 75cm water or above.

EXAMPLE 3 Lap/Shear Strength of Primed and Unprimed Bonds

Adhesion under shear of gel to rat skin was determined on an Instron™apparatus using standard methods. The biological surface was rat backskin, freshly removed from euthanized animals. It was glued to a glassslide, and treated as described below. A casting chamber was positionedabove the skin, which also contained a gauze mesh which protruded fromthe chamber. Monomer solution was injected into the chamber andpolymerized. The chamber was removed, and the tensile strength of thebond was determined by shearing the lap between the glass slide and thegauze mesh in a standard load cell on the Instron™.

Skin treatments included none (control); primed; primed and pre-coatedwith monomer solution by drip; and primed, pre-coated with monomersolution by drip, and rubbed or mixed with a brush. A monomer solutionas in Example 1 was applied, except that the monomer, “8KL5”, had asmaller PEG molecule (8000 D), and was extended with lactate groupsrather than caprolactone groups. With unprimed skin, a differentinitiator, Irgacure™ 651 (Ciba Geigy), was also used in the gellingmonomer mixture.

With the non-primed Irgacure™ system, average load at failure for 6 to 8samples ranged from 49 grams of force with low-intensity mixing ofmonomer onto the surface, to 84 to 274 g. with rubbing. Similar resultswere obtained with the Eosin catalysed system with no primer (146 gaverage, range 80-220) When the tissue was pre-primed with Eosin, andmonomer solution was thoroughly mixed with a brush, the failure forceincreased to 325 g (range 220-420). Thus priming can quantitativelyimprove early adherence, in addition to its much larger improvement inadherence after flexing.

EXAMPLE 4 Sealing of a Bronchus

A bronchus was stapled and cut during lobectomy by the techniquesdescribed for wedge resectioning. The staple line was coated asdescribed in Example 2, likewise preventing or stopping air leaks.

EXAMPLE 5 Sealing of a Laceration

A laceration 2 mm deep by 2 cm long was made on an isolated lung with ascalpel; the scalpel was taped to control the depth of cut. The lung wastested and found to leak. The laceration was primed, filled with monomersolution containing initiator, and the monomer was photopolymerized. Theleak was sealed by this procedure.

EXAMPLE 6 Coating of a Medical Device

A length of polyurethane tubing extrusion used for catheter shafts wasdipped into an aqueous solution containing 20 ppm eosin. Excess eosinwas rinsed off with water. The primed tubing was dipped into a solutioncontaining 10% monomer (type 8KL5, as in example 3), 90 mMtriethanolamine, 5 ppm vinylpyrrolidone, and 20 ppm eosin. Excessmonomer was allowed to drip off. The monomer layer on the tubing wasthen photopolymerized to form an adherent gel coating. The adherence wasstrong enough to survive sectioning of the tubing with a razor blade;photomicrography showed complete adherence of the gel to the tubing. Asa prior art control, the shaft was not primed. After dipping theun-primed shaft into the same monomer solution, the coating on the shaftwas photopolymerized. A gel was formed, but failed to adhere to theshaft, and fell off during handling.

EXAMPLE 7 Priming for Surface Adherence

Two surfaces of Pebax™ polyeteramid were stained with 1000 ppm Eosin Yand rinsed. Polymerizable monomer solution (10% 8KL5 in water containing20 ppm eosin) was placed between the surfaces, and the sandwich wasexposed to green light. Gel formed in the interface and held thesurfaces together. In a control experiment, in which the surfaces werenot primed, polymerization of the monomer occurred but no significantadherence of the surfaces was found.

EXAMPLE 8 Priming of Surfaces

On exposure to 1000 ppm of Eosin Y, surfaces of Teflon™ fluoropolymerand of polyethylene were observed to stain significantly. When monomerwas added to such surfaces, and allowed to stand briefly, gels wereformed on illumination. Adherence seemed inferior to that obtained onpolyurethane.

EXAMPLE 9 Priming of Uterine Horn and Adherence of Gel Layers

A model system was established for placing of barriers on mammalianuteruses after operations. Freshly excised uterine horns from euthanizedpigs were removed from a saline bath and treated with 1000 ppm Eosin.Controls were not primed. Polymerizable monomer solution as in Example 7was applied to the primed and control areas. Adherence of gel layers tothe primed areas was very firm, while gels on control areas could bedislodged.

EXAMPLE 10 Water-sensitive Initiation

It is known to use tributylborane as a water-sensitive initiator of bulkpolymerization. In this example, it is shown that TBB can serve as aninitiator in interfacial polymerization, and thus as a primer.

1 M tributylborane (TBB) solution in THF was purchased from Aldrich.Lyophilized 35KL4A2 reactive monomer containing triethanol amine andeosin was made in these laboratories. Polyethylene glycol 400 (PEG 400)was obtained from Union Carbide). Of the lyophilized powder of 35KL4A2,0.5 gram was dissolved in 9.5 grams of PEG 400. The mixture was warmedusing a heat gun up to 40-50° C. to facilitate dissolution. To thissolution, 30 μL of vinyl pyrrolidinone were added as a comonomer.

Using a glass syringe, 2 ml TBB solution were transferred to a sprayer,of the type used with thin layer chromatography plates. A small amountof TBB solution was sprayed on a glass coverslip and the PEG 400solution containing 35KL4A2 was applied on the TBB solution. Animmediate polymerization of the solution was noticed. The polymerizedfilm was insoluble in water indicating crosslinking.

Similar polymerization was carried out on pig lung tissue. A smallamount of TBB solution was sprayed on approximately 3 cm² of lungtissue. A 35KL4A2 solution in PEG was applied on top of the TBBsolution. A small amount of TBB solution was also sprayed on top of themonomer solution. A well adherent film of 35KL4A2 on lung tissue wasnoticed. The polymerized film was elastic and well adherent to thetissue.

In an alternative procedure, application of the TBB initiator to tissuemay be followed by application of monomer solution containing aphotoinitiator, such as 20 ppm eosin. Photopolymerization is then usedto build a thick layer of gel onto the initiated priming layer. Goodadherence is predicted.

EXAMPLE 11 Combination of Redox Free Radical Initiation Systems withPhotoinitiation and/or Thermal Free Radical Initiation Systems forIncreased Polymerization Speed

Previous visible light photopolymerization of Focal macromonomers usesthe aqueous eosin Y/triethanolamine photoinitiation system. Thisreaction has been observed to generate peroxides when carried out in thepresence of dissolved oxygen in the buffer. One may exploit thesegenerated peroxides as an additional source of free radical initiatorsfor polymerization using a Fenton-Haber-Weiss style reaction. In aneffort to use these formed peroxides as polymerization initiators,ferrous ion in the form of ferrous sulfate was added to the eosinY/triethanolamine buffer and used in the photopolymerization of Focalmacromonomers. Using an indentation style hardness test, gel stiffnessas a function of illumination time was used as a measure of gel cure.

In an experiment to evaluate the effectiveness of 50 ppm ferrous ion onthe gelation of the Focal macromonomer 8KL5, two buffers were prepared.The first buffer was prepared in deionized (DI) water using 90.4 mMtriethanolamine(TEOA) and pH adjusting to 7.4 with 6 N HCl. The secondbuffer was prepared similarly but with the addition of ferrous sulfatesuch that there would be approximately 50 ppm ferrous ion available.These buffers were used to prepare a 10% (w/v) 8KL5 gelling solutionwith 1 microliter of vinyl pyrrolidinone per ml of gelling solutionadded as a comonomer. These solutions were then divided into gellingsamples and had 20 ppm of eosin Y added to them. These samples were thenilluminated using an all lines Ar laser at a power of 100 mW/cm². Allillumination timepoints were done in triplicate and kept dark untilstiffness testing was performed. In comparing a 10%(w/v) Focalmacromonomer gelling solution with and without 50 ppm of ferrous ionadded, the gel with the added iron gave significantly more cured gelsthan did the gel without iron.

It is further believed that any free radical initiation system,especially aqueous ones, capable of generating soluble peroxides can begreatly enhanced by the addition of soluble metal ions capable ofinducing the decomposition of the formed peroxides.

EXAMPLE 12 Redox-accelerated Curing (“Dual Cure”) of Primed Systems

A redox-accelerated system was compared to a purely photoinitiatedsystem for priming tissues. The accelerated system was found to beespecially effective in the presence of blood, which attenuates thelight used in photopolymerization. An acute rabbit lung model of sealingof air leaks was used. A thoracotomy was made under anesthesia in theintercostal space of the rabbit. Anesthesia was induced using anintramuscular injection of ketamine-acepromazine. The seventh rib wasremoved to facilitate access to the lungs, and the animal was maintainedon assisted ventilation. A laceration, about 8 mm×2 mm, was made on eachof the middle and lower lobes of the lung. Air and blood leaks wereimmediately apparent. Bleeding was tamponaded using a gauze sponge, andthe site was then rinsed with saline. Some blood remained, and a slowooze of blood and air leakage from the site was still persistent onventilation.

Two formulations were compared. In the first formulation, the primingsolution contained 500 ppm Eosin Y and 90 mM TEOA (triethanolamine) inWFI (water for injection), while the macromer solution contained 15% w/vmacromer (type 35KL4), 20 ppm Eosin Y, 5 mg/ml vinylcaprolactam, and 90mM TEOA in WFI.

The second formulation contained 500 ppm Eosin Y, 15% 35KL4, and 3 mg/mlferrous gluconate in WFI in the primer, and the same macromer solutionas in the first formulation, supplemented with 500 ppm t-butyl peroxide.

Application methods were the same for both formulations, and consistedof application of 1 ml primer with gentle brushing, followed byapplication of 0.5 ml macromer solution by brushing, and thenillumination with blue-green light at 100 mW/(square centimeter) whiledripping an additional 0.5 ml of macromer. Total illumination time was40 sec. Gels were formed on the tissue by both treatments, and the airand blood leakages were sealed.

Acute adhesion of the gel to tissue was rated on a scale of 1 (poor) to4 (excellent). The first formulation scored 1.5, and the second scored3.5. A notable improvement in adherence of the gel to the living lungswas seen with the use of the dual cure system.

EXAMPLE 13 Optimization of Iron Concentrations

The objective is to find a redox system which does not instantaneouslygel the macromer, and which can also be cured by light. Various formulaewere prepared, and their polymerization was studied.

A stock monomer solution (solution 1) contained 15% w/w “35KL4”macromer, lot 031395AL, in TEOA buffer (90 mM triethanolamine,neutralized to pH 7.4 with HCl, in water for injection), and 4000 ppm VC(vinylcaprolactam) and 20 ppm eosin Y (photoinitiator). The buffer wasselected to be compatible with dissolved iron.

Iron-monomer solution (solution 2) contained in addition 20 mg/ml offerrous gluconate, 5.8 mg/ml of fructose, and 18 mg/ml of sodiumgluconate.

Peroxide primer (solution 3) contained: 500 ppm eosin in TEOA buffer,plus 5 microliter/ml of 10% tertiary butyl peroxide. An alternativepriming solution (3b) contained in addition 10% 35KL4.

Serial dilutions of one volume of iron monomer with two volumes of stockmonomer were made, and the gelation time, in the absence ofhigh-intensity light, upon addition of 1 volume of priming solution (3)to two volumes of diluted iron monomer was determined. The stock ironmonomer and the 1:3 dilution gelled very rapidly (1-2 seconds), and a1:6 dilution gelled in 3-4 seconds. The 1:9 dilution gelled veryslowly—no rapid gelation, and partial gelation after 1 hour. Furtherdilutions (1:27, 1:81) did not gel for at least one hour.

The formulation with 1:9 dilution, containing about 2.2 mg/ml of ferrousgluconate, was tested for its ability to adhere to excised tissue, andto gel in the presence of blood. Acute adherence was obtained with 1:9iron monomer solution when primed with the basic peroxide primingsolution, but better adherence was found with monomer-containing primingsolution (3b).

In solution, a mixture of monomer solution (0.3 ml) and normal primer(0.13 ml; without peroxide), which polymerized when exposed to intenseargon laser light, would not gel after addition of 2 drops of blood(about 33 mg). However, a mixture of the same volumes of 1:9 ironmonomer, primer 3b, and blood gelled in 5 seconds on exposure to thesame light source. Omission of the Na gluconate and fructose did notsignificantly change the gel time. The mixed formulation (iron monomer,peroxide primer, and blood) could be held for three hours in amber glassat room temperature with only slight decrease in the gelling time onexposure to light.

Thus, the formulation is sufficiently stable and controllable underoperating room conditions, so that a preparation could be reconstitutedat the start of the operation, and the material would be useful andapplicable to tissue throughout the operation.

EXAMPLE 14 Adherence to Tissue at Varied Concentrations of Peroxide andIron

Areas of excised fresh or frozen-thawed pig lung were primed with aphotoinitiator, and a gel formed on the spot by dripping ofphotoinitiator-containing monomer. In contrast to the previous example,the iron (ferrous gluconate) was in the primer, and the peroxide in themonomer solution. Gels formed by illumination at peroxide concentrationsranging from 76 to 900 ppm, and iron concentrations ranging from 1500 to5000 ppm, had at least moderate adherence to tissue after overnightincubations.

EXAMPLE 15 Redox Interfacial Primed System

It was demonstrated that non-photopolymerization techniques can producegels adherent to tissue. Thinly-sliced ham was soaked in deionizedwater, and a 1 by 2 inch piece was folded in half and the outer edgeswere bonded together. First, 0.1 ml of solution A was applied to thejoint (Solution A contained 10% monomer 8KL5, 0.3% hydrogen peroxide,and 0.3% NVMA (N-vinyl N-methyl acetamide)). Then 0.2 ml of Solution Bwas applied. (Solution B contained 30% 8KL5, 20 mg/ml Ferrous AmmoniumSulfate hexahydrate (Aldrich), 3% fructose, and 0.3% NVMA. Cure wasinstantaneous, and no discoloration of the gel occurred. The bond heldduring overnight soaking in distilled water.

EXAMPLE 16 Sprayed Redox System

Using the above solutions, and with monomer concentrations varying from5% to 10% in solution A and 10% to 30% in solution B, primer (solutionA) was sprayed on semivertical surfaces, followed by solution B.Surfaces were the palm of the experimenter's hand, and petri dishes. Thespraying procedure caused some foaming, but gels were formed on allsurfaces. Because of running of the solutions down the surfaces, gelswere thicker at the bottom but present throughout. In a similarexperiment, the monomer 8KTMC, containing trimethylenecarbonatebiodegradable linkages between the polyethylene glycol and the acrylatecap, seemed to adhere somewhat better than the 8KLS.

EXAMPLE 17 Comparison of Peroxygen Compounds

Reductant solutions contained 10% 8KL5 monomer and 8% by volume of aferrous lactate solution, which itself contained 1% ferrous lactate and12% fructose by weight in water. Oxidant solutions contained 10% 8KL5monomer and a constant molar ratio of oxidizer, which was, per ml ofmacromer solution, 10 microliters 30% hydrogen peroxide; 8.8 microliterstert-butyl peroxide; 15.2 microliters cumene peroxide; or 0.02 gpotassium persulfate. 0.5 ml of reductant was mixed with 0.25 mloxidizer, and time to gelation was noted. With hydrogen peroxide,gelling was nearly instantaneous, while with the others there was ashort delay—about 1 second—before gelation. Doubling the t-butylperoxide concentration also produced nearly instantaneous gelling.Hydrogen peroxide produced more bubbles in the gel than the others;persulfate had almost no bubbles. The bubbles in hydrogen peroxide maycome directly from the reactant, as the other compounds have differentdetailed mechanisms of radical formation.

EXAMPLE 18 Effect of Reducing Sugars

Using the procedures of Example 17, the concentration of ferrous ion wasreduced to 50 ppm, and the fructose was omitted. At 100 ppm HOOH in theoxidizing solution, gel time was increased to 3 to 4 seconds, with bothFe-gluconate and Fe-lactate, but gels were yellow. Addition of 125 ppmascorbic acid to the reducing solution prevented the formation of theyellow color.

EXAMPLE 19 Sodium Gluconate Addition

It was found that raising the pH of the iron-peroxide system from 3.7 to5.7 by addition of sodium gluconate had no effect on gelation time.

EXAMPLE 20 Compatibility with Ultraviolet Photoinitiators

Solution A contained 1 g 8KL5, 0.4 ml of a ferrous lactate solution(containing 0.4 g ferrous lactate and 4.8 g of fructose in a finalvolume of 40 ml of distilled water), and 8.6 g of distilled water.Solution B contained 1 g of 8KL5, 0.1 ml of 30% hydrogen peroxide, and8.9 g water. Drops of A were allowed to fall into a solution of B,resulting in drops of gel which gradually accumulated at the bottom ofthe solution. If solution B was supplemented with 4% by volume of asolution of 0.2 g of Irgacure™ 651 photoinitiator dissolved (withheating) in 4 ml of Tween™ 20 detergent, then after making bead dropletsas before, the entire solution could be gelled by application of UVlight. This demonstrates the compatibility of the redox and UV-curingsystems. Moreover, it would be possible to make the redox-cured dropletsfrom a monomer which would degrade either faster or slower than thecontinuous-phase gel, as desired, thereby potentially creating amacroporous gelled composite.

EXAMPLE 21 Relative Adherence of Gels

Various gel formulas were compared in their ability to stick to domesticham, versus their ability to adhere the fingers of the hand together. Itwas found that adherence of a formula to one type of surface was onlyweakly predictive, at best, of the adherence to the other. In anotherexperiment, it was found that persulfate-catalysed gels are lessadherent to tissue than comparable t-butyl peroxide gels, but arerelatively more adherent to metal. Thus, the optimal formulation maywell depend on what is to be coated with gel.

EXAMPLE 22 Intra-pleural Sealing

A source of morbidity in lungs is the formation of bullae, which aresacs formed by separation of the plerua from the lung parenchyma. As amodel for possible repair of bullae, the pleura of a detached lung wasrepeatedly nicked to generate small air leaks. Then a solutioncontaining 15% of 35KL18 macromer, 20 ppm of eosin, 5 milligrams/mlvinylcaprolactam, and 90 mM triethanolamine was is injected between thepleura and parenchyma at the sites of the air leaks. The solution spreadpreferentially between the tissue layers, forming a blister-likestructure. The area was transilluminated from the pleural side withblue-green light for 40 seconds. A flexible gel was obtained, and theair leaks were sealed.

A similar procedure could be applied to other layered tissues to stopleaks and effusion. Because the gel is confined within the tissue,adherence to tissue is not a primary concern. There are a number ofanatomical structures having layered tissue structurees suitable forthis method of sealing a tissue against leakage. Such tissue layersinclude the meninges, including the dura, the pia mater and thearachnoid layer; the synovial spaces of the body including the visceraland pareital pleurae, the peritoneum, the pericardium, the synovia ofthe tendons and joints including the bursae, the renal capsule, andother serosae; and the dermis and epidermis. In each case, a relativelyfragile structure can be sealed by injection of a polymerizable fluidbetween adjacent layers, followed by polymerization. Formation of abiodegradable, biocompatible gel layer by non-intrusive processes suchas photopolymerization is especially desirable, because it minimizestrauma to the tissue.

EXAMPLE 23 Sealing of an Injured Artery.

In an anesthetized pig, a 1.5 cm lengthwise incision was made in acarotid artery. The incision was closed with interrupted sutures, sothat blood seepage occurred. The injured area was rinsed with saline,and the blood was suctioned from the treatment zone. The treatment zonewas primed with 1 mg/ml eosin in buffer (TEOA in 1/3 normal phosphatebuffered saline). A macromer solution was applied with a smallpaintbrush to the treatment zone under illumination with blue-gree argonion laser light. In a first artery, the macromer solution contained 15%35KC3.3, 4 mg/ml N-vinylcaprolactam, and 20 ppm eosin. In a secondartery, the macromer was type 35KL18, and the macromer solution has apaste-like consistency. Four applications (0.5 to 1.0 ml each) wererequired to seal all leaks. It was easier to build thickness with thepaste-like monomer. The pig was held under anesthesia for an hour, andthe injury sites were reexamined and found to be still sealed.

EXAMPLE 24 Adherence of Coating Layers to Living Tissue Surfaces

An experiment was performed to evaluate the acute adherence of aformulation of 20% macromer 35KTMC8A2 with redox/eosin primer touninjured tissue in situ. An immature pig (est. 35 kg) was maintained inan anesthetized condition and various tissues and prosthetic implants(described below) were surgically exposed or prepared. Care was taken toprevent injury to the tissues; however, the dissection of connectivetissue often resulted in a roughened surface where the primer/polymerwas applied.

The primer and macromer were applied with separate paint brushes, andlight was delivered from a bare 2 mm diameter optical fiber. The lightsource was periodically checked and consistently emitted approx. 580 mWof visible light through the course of the experiment at the distal tipof the delivery fiber.

The acute adherence was graded on a 1-4 scale, where 3 or better isconsidered acceptable: “4”: cohesive failure into small pieces when thedeposited gel is gripped with blunt tweezers and pulled perpendicularand/or parallel to the tissue surface.

“3”: cohesive failure with larger fragments.

“2”: combined cohesive/adhesive failure.

“1”: adhesive failure, gel lifts off in continuous film.

A. Adherence to Tissues (Tissue/Adherence grade):

1) Lower stomach (proximal to pylorus)—3.5. The stomach was reexaminedafter 1 hour indwelling—<3.5. Still adherent, but less than at time=0.Tear strength deteriorated.

2) Common bile duct—3.5.

3) Urinary bladder—3.8 (Punctate bleeding was noted on the bladder; itwas confirmed that the causes were brushes and manipulation).

4) Ureter—3.5-3.8;

5) Large bowel (descending colon 8 cm anterior to pubic bone)—4.0

6) Esophagus 3.5.

7) Patellar tendon (2 cm proximal to tibial attachment)—3.5

8) Cartilage (trochlea groove of knee)—2.5. This tissue didn't stainwith eosin; polymerized gel peeled off in sheets. Removal of upperhyaline layer, deep enough for minor blood oozing to appear, improvedscore to 2.8.

B. Adherence to Other Implantable Materials.:

9) Collagen coated Dacron patch—3. This was a Datascope woven Dacrongraft material 8 mm diameter. Collagen impregnated; 6-0 Prolene sutures.

10) Abdominal aortic graft—3.5. This was a Meadox Dacron double velour(inside/outside); 6 mm Inside diameter; Cat No. 174406. Lot No 245246.Sterilized 1986. The graft was preclotted in autologous blood. Theanimal was heparinized before implantation.

11) Gore FEP (fluorinated ethylene propylene) in vitro test—0. Materialwould not stain; cured polymer slid off without effort.

12) Carotid Gore patch—2.5-3. Polymer adhered to sutures and surroundingtissue.

13) Hernia mesh—2.5 (more or less). Polymer was used to anchor the mesh(by U.S. Surgical) onto external abdominal oblique fascia. The polymerwas suitable for positioning, but did not provide “structural”anchoring.

EXAMPLE 25 Process for Sealing Medical Devices to Body Tissues

There is a need to seal or bond medical device surfaces to tissue. To besuccessful, this application requires the sealant or adhesive to formstrong bonds to both the device and the tissue. Important examples ofthis application apply to sustained use devices such as percutaneouscatheters (e.g. central venous catheters), percutaneous cannulae (e.g.for ventricular assist devices), urinary catheters, percutaneouselectrical wires, ostomy appliances, electrodes (surface and implanted)and the like. In such devices, there is a tendency of the implant ordevice to move relative to the surrounding tissue. Such movement canallow entry of microorganisms, or can intensify the reaction of thetissue to the implant. Moreover, when a device is insertedpercutaneously, then during the process of healing the epidermis incontact with the implant may undergo “marsupialization”, or theformation of a partial pouch along the surface of the implant. This canretard healing of the percutaneous opening, following removal of thedevice.

In scope, the process includes sealing the device/tissue interface forany medical device that crosses or disrupts a tissue layer whosecontinuity provides a natural defense mechanism against infection orbodily fluid loss (skin, mucous membranes). This technology is alsoapplicable to obliterating potential space between implanted devicesthat do not allow tissue ingrowth/ongrowth and the implant bed, servingto reduce device movement which is a cause of chronic inflammation.These tissue-device sealants may also serve as matrices for drugdelivery, for example the delivery of antimicrobials to preventinfection.

Bioabsorbable hydrogels and non-absorbable analogs are appealing forthese applications in that they may be formed in place to seal (or“caulk”) around the device. Hydrogels usually adhere poorly tohydrophobic device surfaces which comprise most of the examples listedabove.

However, a process is provided herein which produces a strong attachmentof hydrogel to a hydrophobic surface during in situ polymerization ofhydrogel components. It involves applying a primer containing adequateconcentrations of an initiator of polymerization (Eosin Y and/or otheringredients) to a hydrophobic surface (in the example below,polystyrene, in a 12 well plate) following with a sealant compositionbased on a polymerizable macromer (in this example containingtriethanolamine co-initiator), and effecting polymerization. Thedifferent embodiments, 25.1-25.3, are described below.

25.1: Into one well of a 12 well microtiter dish was placed 0.1 ml of aprimer solution containing 500 ppm eosin with ferrous gluconate (5mg/ml), fructose(10 mg/ml), and macromer 3.3KL5A2 (30%). Then 0.9 ml wasadded of a solution containing 12.8% of macromer F127T4A2 (i.e.,poloxamer Pluronic F127, with 4 units of trimethylene carbonate andacrylate end caps), 125 ppm t-butyl peroxide, 90 mM triethanolamine and0.4% VC (N-vinylcaprolactam). The mixture partially gelled on mixing,but the gel was not coherent. After illumination with blue light for2×20 sec., a coherent gel was formed. However it was not tightly adheredto the surface of the plastic.

25.2: The experiment was repeated, but the eosin concentration wasraised to 2000 ppm. Initially the solution did not gel as well, but onillumination the gel adhered strongly to the plastic.

25.3: The experiment was repeated at 2000 ppm eosin concentrations, butwithout the “redox” components (ferrous gluconate, fructose, t-butylperoxide). Adherence was stronger at 2000 ppm eosin (alone) than at 500ppm even with redox materials, although not as strong as with the redoxcomponents present.

The results are compatible with the idea that the eosin was absorbing tothe surface of the plastic during the course of the experiment. Tovalidate this, a solution containing 12.8% macromer (F127T4A2), theusual VC and buffer, no redox components, and 2000 ppm eosin was appliedto a well and allowed to stand for about 10 seconds. The gel wasstrongly adherent. In a comparable experiment at 100 ppm eosin, the gelwas formed but adhered weakly.

Thus, a critical variable here appears to be the level ofphotoinitiator—here eosin—in the primer. Relatively high concentrations(2000 ppm) gave stronger bonds of hydrogel to polystyrene than loweramounts. The use of “redox” coinitiators gave stronger gels, but highEosin levels gave strong bonds with or without “redox” coninitiation.

In other experiments, it was demonstrated that the system that gave thestrongest bonds to the polystyrene also gave very strong bonds to animaltissue (cadaveric goat gingiva). The strong bonding of sealant topolystyrene 12 well plates may thus used (in the absence of tissue)todemonstrate the tissue bonding capability of a particular hydrogel, thusminimizing experimentation. This system, applied simultaneously to atissue and a hydrophobic device (via application of primer, sealant, andlight) would thus appear to result in an effective tissue-to-devicesealant with wide-ranging applicability.

EXAMPLE 26 Use of Redox-assisted Photoinitiation in Treatment of InjuredArteries

The interior of a rabbit carotid artery was injured by scraping with aninflated balloon catheter. The injured area was then isolated with a twoballoon catheter, and the injured zone was flushed with saline; stainedon its surface with an initiator solution, containing 20 ppm eosin Y inPBS (phosphate-buffered saline, pH 7.4);further flushed with saline toremove unbound eosin;treated with a buffered solution containing 90 mMTEOA (triethanolamine), pH 7.4; 30% by weight of polymerizable macromer;0.2% to 0.25% of vinylpyrrolidone or vinylcaprolactam; and optionally 50ppm of ferrous sulfate. The treatment zone was then exposed to 100mW/sq. cm.of green light from an argon laser for 20 seconds. Theballoons were collapsed and blood flow was permitted to resume,resulting in flushing of excess macromer from the zone into the rest ofthe circulation. In various tests, it was found that a thin layer of gelwas formed on the inside of the artery both with and without theaddition of ferrous ion. It was further found that the layer persistedfor longer times in the presence of the ferrous ion.

To better understand this system, gels were formed in test cells, andtheir mechanical properties after various lengths of illumination werecompared. It was found that the addition of iron resulted in gels whichwere better cured and which were relatively less sensitive to the exactconcentration of other reagents, or to the duration of illumination.This is shown in more detail in Table 1:

TABLE 1 Ratio of Modulus at 20 sec. to 90 sec. of illumination 20 100Redox ppm ppm Illumination conc. eosin eosin 100 mW/cm2 50 ppm Fe 93%83%  0 ppm Fe 63% 14% 400 mW/cm2 50 ppm Fe 98% 77%

Conditions: 30% 3.3KL5 in 90 mM TEOA pH 7.4 and 2 μL VP/mL.

The ratio of the gel modulus at 20 sec. illumination to 90 seconds is ameasure of the rapidity of complete polymerization of the gel. Highernumbers denote faster polymerization. It can be seen that the additionof iron markedly accelerates the cure, and that this effect is morepronounced at 100 ppn eosin, where the underlying variation is greater,and likewise at lower light levels.

EXAMPLE 27 Redox Systems with Urethanes, Acids and Amides, using CericIon

The objective of the experiment was to determine the feasibility ofmaking polar-ionic macromers using a Ce-IV based redox system withurethanes, carboxylates or amides as reductant. A special macromer wasmade (3.3KL5A1: 3.3K PEG; 5 lactides; 1 acrylate) and end-capped withdiisocyanate to form a urethane by standard procedures.

The different embodiments, 27.1-27.4, are described below.

27.1: Add 1 ml of methacrylic acid to 10 ml of 2.25 wt. % Ceric ammoniumnitrate in water (“Ce solution”; has yellow color). A white precipitatewas formed immediately; the yellow color faded over time.

27.2: Add 10 ml Ce solution to a 10 ml solution containing 0.5 ml aceticacid and 0.5 ml methyl acrylate. A white precipitate formed immediately,and the yellow color gradually faded.

27.3: Add 1 g of the NCO-end capped initiator to 10 ml of Ce solution,and mix with 10 ml of a 50% w/v solution of AMPS (acrylamido methylpropanesulfonic acid). The solution remained yellow and unprecipitated.However, after standing overnight at room temperature the solution hadbecome colorless and highly viscous, and was not filterable through a0.2 micron filter. This suggests a high degree of polymerization,perhaps with some crosslinking.

27.4: A carboxylate-terminated macromer was made by treating 3.3KL5A1.0with succinic anhydride. The purified reprecipitated polymer wasdissolved in deionized water (0.39 g /7 ml) and 2.0 g of AMPS was added.The pH was adjusted to 3.8 with NaOH. Then 55 mg. of Ce(IV) ammoniumnitrate was added (approximately stoichiometric with the expected numberof carboxyl groups). The volume was adjusted to 10 ml. with water. Thesolution rapidly became turbid and increased in viscosity, and appearedto be crosslinked to a gel within about 1 hr. The resulting gel could bedissolved by pH 13 NaOH solution in about 1 hr., showing that thecrosslinks involved the degradable ester moieties.

It appeared that both carboxylic groups and urethane groups can serve asreductants for ceric ion in a redox-catalysed polymerization of anunsaturated group. Other groups known to be effective in such reactionscan also be used where the conditions are physiologically reasonable.

EXAMPLE 28 Adherence of Medical Device Material to Tissue

In this example, direct adhesion of a typical medical polymer to tissueis demonstrated. It is further shown that the location of the plane offracture of the composite can be controlled by selection ofconcentration and type of photoinitiator.

Microscope-slide-sized pieces of Pellethane (Dow) extruded polyurethanesheet were washed with acetone to remove impurities and dried in avacuum oven. They were then stained with a solution of 2000 ppm Eosin Yin PBS, as above, for several minutes until pink staining of thepolyurethane was observed. Sheets were rinsed in water and air dried.

Pieces of abdominal wall were excised from a euthanized rat, and usedwith the peritoneal side “up” (“tissue”) Tissue was clamped to a glassslide with binder clips. Thin Teflon spacers were placed on top of thetissue. Dried sheets of urethane were clamped into the sandwich,eosin-stained side towards the tissue, forming a thin chamber betweenthe polyurethane and the tissue, typical of clearances found in medicalpractice. Four combinations of solutions were tested.

The different embodiments, 28.1-28.4 are described below.

28.1: About 0.2 ml of a primer solution containing 2000 ppm eosin in PBSwas infused into the chamber, and was removed by wicking after about aminute. A macromer solution (about 0.2 ml) was added, containing 12.8%F127T4A2 macromer (as in example 27), 90 mM TEOA and 0.4% VC (vinylcaprolactone), and, is in this experiment, 2000 ppm eosin. The chamberwas transilluminated through the glass slide and rat flap for 40seconds. The macromer did not completely polymerize, and on removal ofthe clamps the tissue separated from the urethane without appreciableforce.

28.2: The above experiment was repeated, but the eosin concentration inthe macromer solution was reduced to 20 ppm. Polymerization wascomplete. On separation of the tissue from the urethane, the gelfractured while remaining adherent to both tissue and to the urethane.

28.3: The above experiment 28.2 was repeated, except that the redoxaccelerator t-butyl peroxide was present in the macromer solution at 125ppm, and the primer contained Ferrous gluconate and fructose as inExample 25.1. The gel was completely polymerized. On attempting to peelthe tissue from the urethane, the tissue tore—i.e., both the gel and itsbonds, to both tissue and device, were stronger than the tissue itself.

28.4: Experiment 28.2 was repeated, except that the concentration ofeosin in the primer was reduced to 20 ppm. Polymerization was complete.On peeling the tissue, failure of adhesion occurred at the interfacebetween the gel and the tissue.

This example demonstrates that by selection of initiator types andconcentrations, the fracture plane of a device bonded to a tissue by agel can be varied at will, and behaves in a reasonable and predictableway. Although the gel compositions in this example were degradable, thepeeling was done at short times, and the results will extrapolatedirectly to non-degradable gels.

In the following Examples 29-30, the following methods and parameterswere used:

Elongation to Fracture and Young's or Other Elastic Modulus

Samples are prepared in a mold to have the required concentration ofmonomer and other ingredients. The crosslinked or otherwise curedspecimens are placed in an appropriate machine, such as an Instron™tester, and the force required to stretch the sample along a single axisis measured as a function of the distance the sample is stretched(strain). Elongation may be continued until the sample breaks, givingthe value for elongation at break, optionally after cycling at lowerelongations to determine the degree of any plastic deformation of thesample. The data (force vs. distance) may be recorded and used to make aplot, as in FIG. 1. Because the response of a particular material is notnecessarily “ideal”, especially at high elongation, a modulus may becalculated from values at low degrees of elongation where the behavioris closer to linear. Alternatively, the force vs. strain values may beused directly without extrapolation, or without division by samplethickness to give the “normalized compliance” discussed above.

Bulk Compression Modulus

The sample of gel or tissue is placed in a suitable instrument, such asa Perkin-Elmer DMA 7e, and the modulus is measured according to astandard procedure. A gel sample could also be polymerized directly inthe instrument for testing.

Adhesive Strength

This was tested by a lap shear test. The test sealant material was usedto adhere a 1 cm×1 cm area of two pieces of test substrate, typically astandardized tissue such as rat peritoneum or pig pericardium. Aftercrosslinking or curing of the test material, the force required to breakthe adhesive bond was determined using a suitable instrument, such as anInstron™ tester. In one variant of the test, three pieces of substratewere adhered: a center piece, with tab extending in one direction, and apair of outer pieces with tabs extending in the opposite direction;sealant was used to join all three pieces. Either arrangment also can beused to determine the relative mechanical properties of various samples(i.e., compared to standards) at small displacements, which is usefulwhen only limited sample volume is available.

Adherence

Adherence of sealant formulae in vivo is determined qualitatively, bythe relative resistance of the sealant to displacement from itsdeposition site by a probe.

Viscosity

Viscosity was measured by standard methods, typically in a Brookfield™viscometer.

Seal Pressure Testing

Seal Pressure Testing was performed by punching a 3 mm round hole in astandard tissue, such as pig pericardium, and mounting the tissue as theclosure in a test fixture. Sealant was applied to the hole and cured,typically in a spiral pattern, to obtain closure of the hole. Thenincreasing pressure was applied to the transverse side of the tissueuntil the plug of sealant was displaced.

Sealant Polymerization

In Examples 29-30 below, a preferred formulation of the sealing systemwas used. When applied to tissue or to a surface to which adherence wasrequired, the surface was primed with a mixture which contained byweight approximately 65% water, 30.4% of a polymerizable macromer(3.3KL5A2, a 3.5 kD polyethylene glycol backbone carrying an average of5 lactate groups and end capped with acrylate), 3% NaCl, 1% fructose,0.5% ferrous gluconate, and 0.2% Eosin Y. The primer was applied to thesurface and spread with a brush. Then about 2 volumes of sealantsolution was applied and mixed with a brush. The sealant contained about77% water, 20.5% polymerizable macromer 35KTMC8A2 (35 kD polyethyleneglycol carrying an average of 8 trimethylenecarbonate groups and endcapped with acrylate), 1.1% triethanolamine, 1% KH2PO4, 0.4%vinylcaprolactam, 0.013% t-butyl hydroperoxide, and 0.002% Eosin Y. Whenthe sealant solution was tested in isolation, the t-butyl hydroperoxidewas omitted. The sealant system was photopolymerized by exposure toblue-green light for about 40 sec.

EXAMPLE 29 Elasticity Results

Using the materials described above, lap shear testing samples wereprepared by applying the macromer solution with a cotton swab to a 1cm×1 cm area on a 3 cm×1 cm strip of rat peritoneal tissue, then layingthe other strip of the same size on top as to make a sandwich. Thesample was then transilluminated from the top and then the bottom for 40sec each. Lap shear testing was performed using a 12.5 mm gauge length.Tensile testing using a sample size of 45 mm×10 mm×5 mm and a 12.5 mmgauge length, was performed. DMA (Perkin Elmer) testing with a sampleheight of 1.6 mm was performed at 37° C. after hydrating for 2 hours insaline at 37° C. A subjective scoring system was used to assessadherence in a goat lung model on a scale from 1-4 (1=poor adherence &4=excellent adherence).

In Vitro Testing

This synthetic surgical sealant could be rapidly polymerized withvisible light to form a flexible hydrogel. As can be seen from thetensile data in FIG. 1, this material showed a completely elasticdeformation profile with linear elongation at break in excess of 700%.The polymerization process of this material and the properties of lungtissue and muscle tissue were studied using the dynamic mechanicaltester. It was seen that muscle tissue, as expected, had a highermodulus than spongy parenchymal lung tissue. The sealant material wascured within 40 seconds and reached a final modulus very comparable tothat of the lung tissue. This ensures a compliant and persistentadhesive bond. The bond strength was determined using the lap shear testapparatus and the material was seen to form a strong yet flexible bondto tissue. This bond strength is in excess of literature values forfibrin glues in comparable tests. Table 1 shows a summary of in vitroresults.

In Vivo Testing

All goats that had undergone the thoracotomy procedure survived thesurgery uneventfully. Goats were sacrificed at timepoints of 14 days, 1month, and 3 months. At all timepoints, the hydrogel was seen to be firmand clear and had an adherence score of 3.0-3.5 out of 4.0. No tissuenecrosis was evident. Histological sections of the tissue showed normalhealing. The results are shown below in Table 2.

Table 2: In-Vitro Testing Summary

Property; Result

Compressive modulus at full cure, sealant; 32.4 kPa

Compressive modulus of lung tissue, pig; 27.5 ±3.4 kPa

Compressive modulus of lung tissue, dog; 28.0 ±1.9 kPa

Modulus of rat muscle tissue; 73.4±6.8 kPa

Young's modulus at full cure, sealant; 29.4 kPa

Elongation at break, sealant; 788±255.2%

Sealant lap shear strength; 90.17±18.17 g/cm²

EXAMPLE 30 Comparative Results

Tissucol™ sealant is a commercial fibrin sealant used in Europe. It isnot at present approved for use in the United States, in part because itis made from human serum and thus may carry infectious agents. Tissucolsealant was used according to its manufacturer's directions. Incomparison to the preferred sealant formulation of the previous example,the following results were obtained shown in Table 3:

TABLE 3 Properties of Sealants FocalSeal ™ Tissucol ™ Test: SealantSealant A. Double lap shear 38 ± 6 kPa 10 ± 6 kPa B. Compression Modulus32 ± 1 kPa 35 ± 5 kPa C. Viscosity ≈780 cP at 20%  117 cP conc.(fibrinogen)  1.6 CP (thrombin) D. Seal Pressure Test ≈380 ± 100 ≈30 mmHg ±20 mm Hg

When applied to a living dog lung, the fibrin sealant had an adhesionscore of 1, and leaked on all staple lines at 10-40 mm Hg. It wasdifficult to apply the fibrin material to a punch-type leak, because airbubbles coming through the leak tended to remove the material before itpolymerized. In contrast, sealant adhered to primed tissue with anadhesion of 3.5, and typically withstood 80 mm Hg or more of pressure.Its high viscosity slowed bubble penetration.

The optimal material for lung, as described above, has an elongation atbreak of over 700%. Other materials were suitable, if less optimal. Fornon-collapsed lung, a material (20KT8A2) with an elongation at break of225% was suitable, while a material (8KL5A2) with an elongation at breakof 100% (and an elastic modulus of 47±4 kPa) was not effective in lung.The expansion of a dog lung was measured. It was found that theeffective area expansion during a normal breathing cycle is about 200%,while the expansion from the atalectatic (collapsed) state to fullinflation changed area by about 300%. In the latter case, an extension(strain) of about 100% was observed along one axis, and about 200% alonga perpendicular axis, implying non-uniformity of the tissue structure.

Thus, an important requirement for a sealant system on this tissueappears to be that the normalized compliance of the sealant is greaterthan the normalized compliance of the tissue to which it is applied.While the lung is perhaps the most dramatic example of tissue elasticityand area expansion during normal physiological processes, other tissues,such as the bowels, the bladder and large arteries, can change surfacearea substantially during normal physiological cycles. Other tissues,such as the beating heart, exhibit significant changes in shape (shear)without necessarily changing local area.

The compliance of the sealant may be selected depending on the tissue towhich it is to be applied. A sealant having a high value of normalizedcompliance, or a low value of the normalized compliance ratio(tissue/material), may be beneficial for certain applications. Forexample, the 700% —elongation low-modulus material described above isalso suitable for sealing the dura of the brain, or the spinal cordafter laminectomy, even though these tissues are relativelynon-compliant (i.e., are difficult to stretch). Thus, high normalizedcompliance sealant appears to be useful on most tissues, and desirableas a material having a broad range of applications.

What is claimed is:
 1. A device comprising on its surface a compliant polymeric material, wherein the material is formed by the polymerization of an aqueous solution or suspension of a polymerizable monomer in contact with the surface which has been primed by application of an initiator.
 2. The device of claim 1 wherein the material further comprises a biologically active material.
 3. The device of claim 2 wherein the biologically active material is selected from the group consisting of proteins, peptides, organic synthetic molecules, inorganic compounds, nucleic acids, lipids, steroids, carbohydrates, and combinations thereof.
 4. The device of claim 3 wherein the biologically active material is selected from the group consisting of hyaluronic acid, hormones, antibodies, enzymes, antibiotics, and genes.
 5. The device of claim 1, wherein the material is biodegradable.
 6. The device of claim 1, wherein the compliant polymeric material has an adherence to the surface of the device of at least 20 grams per square centimeter.
 7. The device of claim 1, wherein the normalized compliance ratio of the material and the surface of the device is in the range of about 0.05 to about
 3. 8. The device of claim 7, wherein the normalized compliance ratio of the material and the surface is greater than
 1. 9. The device of claim 1, wherein the device is selected from the group consisting of a medical device, an implant, and a wound dressing.
 10. The device of claim 9, wherein the surface is a surface of a medical device, selected from the group consisting of percutaneous catheters, percutaneous cannulae, urinary catheters, percutaneous electrical wires, ostomy appliances, and electrodes.
 11. The device of claim 9 wherein the device is a stent.
 12. The device of claim 9, wherein the surface is a surface of a medical implant selected from the group consisting of pacemakers, defibrillators and tissue augmentation devices.
 13. The device of claim 1, wherein the material comprises biodegradable regions.
 14. The device of claim 13, wherein the biodegradable regions are selected from the group consisting of poly(alpha-hydroxy acids), poly(amino acids), polycarbonates, poly(anhydrides), poly(orthoesters), poly(phosphazines) and poly(phosphoesters).
 15. The device of claim 1 wherein the initiator is a photoinitiator.
 16. The device of claim 1 wherein the polymerization reaction occurs between at least one first reactant selected from the group consisting of an amine, an alcohol, and a thiol and at least one second reactant selected from the group consisting of an isocyanate, an isothiolcyanate, an aldehyde, an epoxide, an oxirane, and a cyclic imine. 